EP3066090A1 - 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use - Google Patents

4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use

Info

Publication number
EP3066090A1
EP3066090A1 EP14796082.7A EP14796082A EP3066090A1 EP 3066090 A1 EP3066090 A1 EP 3066090A1 EP 14796082 A EP14796082 A EP 14796082A EP 3066090 A1 EP3066090 A1 EP 3066090A1
Authority
EP
European Patent Office
Prior art keywords
pyrazol
fluoro
indol
indole
piperidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14796082.7A
Other languages
German (de)
English (en)
French (fr)
Inventor
Stefano Crosignani
Sandra CAUWENBERGHS
Frederik Deroose
Gregory DRIESSENS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Iteos Belgium SA
Original Assignee
Iteos Therapeutics SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/076,016 external-priority patent/US9126984B2/en
Application filed by Iteos Therapeutics SA filed Critical Iteos Therapeutics SA
Priority to EP14796082.7A priority Critical patent/EP3066090A1/en
Publication of EP3066090A1 publication Critical patent/EP3066090A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel 4-(indol-3-yl)-pyrazole derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof.
  • Compounds of the invention are inhibitors of TD02 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancers.
  • tryptophan an essential amino acid, is catabolized in the local microenvironment of tumors, immune- privileged sites, or sites of inflammation (Mellor AL and Munn DH., Nat Rev Immunol, 2008, 8, 74-80).
  • cancer cells In these tissues, cancer cells, immune cells, or specialized epithelial cells (e.g., syncytiotrophoblasts in the placenta) create an immunosuppressive environment in tumors that shut down antitumor immune responses in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites (Munn DH et al., J Exp Med., 1999, 189, 1363-1372; Fallarino F et al., Cell Death Differ., 2002, 9, 1069-1077).
  • epithelial cells e.g., syncytiotrophoblasts in the placenta
  • tryptophan 2,3-dioxygenase which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in a wide variety of cancers, such as for example in bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic carcinoma (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
  • TD02 expression in tumor cells prevents tumor surveillance by the immune system and thus prevents tumor rejection by locally degrading tryptophan (Opitz CA et al., Nature, 2011, 478(7368), 197-203).
  • the first evidence for this was provided through inhibition of TD02 by a small molecule which inhibited tumor growth in a P815 mastocytoma tumor model with a prophylactic vaccination approach (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
  • P815mTD02 expressing tumors were rejected less in comparison to P815 tumors transfected with an empty vector, clearly demonstrating a growth benefit for TD02 expressing tumors.
  • TD02 In line with its expression profile in liver, TD02 was found predominantly in hepatocellular carcinoma (HCC) (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502). Inhibition of tryptophan catabolism and thus restoration of tryptophan concentration and decreased production of downstream metabolites could prove beneficial in the context of liver disease progressing to the stage of liver carcinoma: (i) several reports have shown evidence that increased availabillity of tryptophan through supplementation is beneficial for eg cirrhotic livers allowing the direct use of tryptophan for protein synthesis (Ohta et al., Amino Acids, 1996, 10(4), 369-78); (ii) there is a correlation between increased downstream serum tryptophan metabolites, such as quinolinic acid, and hepatic dysfunction in patients with liver cirrhosis (Lahdou et al., Hum Immunol, 2013, 74(1), 60-6) (ii
  • RNA expression is a good indication for therapeutic evaluation of TD02 inhibitors (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502). The above thus provides a clear rationale for TD02 activity modulation in the control of liver tumor development.
  • TD02 In addition to expression in liver, TD02 is expressed in neurons, microglia and astrocytes and the potential benefit of TD02 inhibition in the context of glioma was shown in another animal model. Platten and collaborators demonstrated that the tryptophan catabolite kynurenine produced by TDO expressed in the tumor cells suppresses antitumour immune responses and promotes tumor-cell survival and motility through the AHR in an autocrine/paracrine fashion (Opitz CA et al., Nature, 2011, 478(7368), 197-203). The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival.
  • TD02 mRNA tumor types in which TD02 mRNA was found are breast carcinoma, bladder, renal cell, pancreatic, colorectal, head & neck carcinoma and lung carcinoma as well as melanoma thus broadening the scope of TD02 targeting beyond HCC and glioma (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
  • tryptophan catabolism in some cancers might be also increased by the expression of indoleamine 2,3-dioxygenasel (IDOl) by tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269-1274). Because tryptophan catabolism is induced by inflammatory mediators, notably IFN-gamma, it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology.
  • IDOl indoleamine 2,3-dioxygenasel
  • TD02 inhibitors were proposed in WO2010/008427 and by Dolusic, E. et al. (Dolusic et al., J. Med. Chem., 2011, 54, 5320-5334), however either their affinity for the target is limited, or their pharmacokinetic properties are not suitable for development as a drug for human use. Therefore, there is a need for new TD02 inhibitors with improved efficacy for cancer treatment and/or prevention.
  • the present invention provides new TD02 inhibitors which may be administered to any patient diagnosed with cancer, or any subject being at risk of developing a cancer.
  • This invention relates to compounds of Formula I:
  • X 1 and X 2 represent each independently H, halogen or haloalkyl, preferably H, F or CF 3 , more preferably H or F;
  • M and Q represent each independently H, halogen, hydroxyl, C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, 1 2 1 2
  • R 1 and R 2 represent each independently a group, optionally substituted, selected from C 1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl; preferably M and Q represent each independently H, methyl or CF 3 , more preferably H or methyl;
  • A represents:
  • aryl optionally substituted with halogen, hydroxyl, nitro, amido, carboxy, amino, cyano, haloalkoxy, haloalkyl, alkyl;
  • heteroaryl optionally substituted with halogen, hydroxyl, nitro, amido, carboxy, amino, cyano, haloalkoxy, haloalkyl, alkyl; preferably substituted or unsubstituted pyridyl or pyridazine, more preferably substituted or unsubstituted pyridyl;
  • CI -C IO alkyl linear or branched, optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, COOR 1 ,
  • R 1 and R 2 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, heteroaryl, amino;
  • heterocyclyl preferably selected from azetidine, piperidine, morpholine, piperazine, tetrahydrofurane, tetrahydropyrane, tetrahydro-thiopyran- dioxide, dioxane, imidazolidinone, pyrrolidine, pyrrolidinone; optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 , CONR ⁇ 2 , NR ⁇ OR 2 , NR X R 2 , S0 2 R ⁇ SOR 1 , wherein R 1 and R 2 represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optional
  • C1-C3 alkyl-heterocyclyl preferably selected from azetidine, piperidine, morpholine, piperazine, tetrahydrofurane, tetrahydropyrane, tetrahydro- thiopyran-dioxide, dioxane, imidazolidinone, pyrrolidine, pyrrolidinone; wherein both the C1-C3 alkyl and the heterocyclyl are optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 ,
  • R 1 and R2 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, S0 2 Me;
  • cycloalkyl preferably cyclobutane or cyclohexyl, optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 ,
  • R 1 and R2 represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, S0 2 Me;
  • C1-C3 alkyl-cycloalkyl optionally substituted with up to three substituents selected from the group comprising alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, alkoxy, COOR 1 , COR 1 ,
  • R 1 and R 2 represent each independently a group selected from Cl- C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, S0 2 Me.
  • compounds of the invention are of Formula I as defined above, under the condition that the compound of Formula I is not:
  • group A is not H. According to a another specific embodiment, when X 1 , X 2 and Q are hydrogen atoms in formula I, then, group A is not H.
  • group A is not an optionally substituted aryl group, more specifically, group A is not an optionally substituted phenyl group.
  • group A is not an optionally substituted aryl group, more specifically, group A is not an optionally substituted phenyl group.
  • group A is not a CI -CIO alkyl, preferably, group A is not a C1-C4 alkyl, more preferably, group A is not methyl, ethyl or butyl.
  • group A is not is not a CI -CIO alkyl, preferably, group A is not a C1-C4 alkyl.
  • group A is not a substituted CI -CIO alkyl, preferably, group A is not a substituted C1-C4 alkyl, more preferably, group A is not a substituted ethyl.
  • group A is not a substituted C1-C10 alkyl, preferably, group A is not a substituted C1-C4 alkyl, more preferably, group A is not a substituted ethyl.
  • preferred compounds of Formula I are those of Formula la:
  • X 1 and X 2 represent each independently H, halogen or haloalkyl, preferably H, F or CF 3 , more preferably H or F;
  • M and Q represent each independently H, halogen, hydroxyl, C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R2 , NR 1 COR2 wherein R 1 and R 2 represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl; preferably M and Q represent each independently H, methyl or CF 3 , more preferably H or methyl;
  • Y 1 and Y2 represent each independently CR 7 , N, O, S0 2 , wherein R 7 represents H or hydroxyl;
  • R represents H, alkyl
  • R , R , R and R represent each independently H, hydroxyl, alkyl, alkoxy, haloalkyl or 4 4' gether an oxo moiety or 5 5'
  • R and R form to R and R form together an oxo moiety
  • R 6 is absent or represents H, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, COR 1 , COOR 1 , CONR ⁇ 2 , NR ⁇ OR 2 , NR R 2 , SO 2 R 1 , S0 2 NR 1 R 2 , NR 1 S0 2 R 2 , SOR 1 , wherein R 1 and R 2 represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, S0 2 Me.
  • preferred compounds of Formula I are those of Formula Ia-1:
  • X 1 and X 2 represent each independently H or F;
  • M and Q represent each independently H, C1-C6 alkyl optionally substituted by one or more halogen;
  • Y represents N or CH
  • R , R , R and R represent each independently H, hydroxyl, alkyl, alkoxy, haloalkyl or 4 4' ogether an oxo moiety or 5 5'
  • R and R form t R and R form together an oxo moiety, preferably 4 4' 5 5'
  • R , R , R and R represent H or oxo;
  • R 6 represents H, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; cycloalkyl, halogen, hydroxyl, oxo, COOR 1 , COR 1 ,
  • R 1 and R2 represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, S0 2 Me; preferably R 6 represents H, COOH, COMe, CONH 2 , CONHMe.
  • preferred compounds of Formula I are those of Formula Ia-2:
  • X 1 and X 2 represent each independently H or F;
  • M and Q represent each independently H, C1-C6 alkyl optionally substituted one or more alogen;
  • Y represents N or CH; preferably Y is N;
  • R 4 , R 4 ', R 4 ", R 4 '", R 5 , R 5 , R 5 " and R 5 '” represent each independently H, hydroxyl, alkyl, alkoxy, haloalkyl or R 4 and R 4' form together an oxo moiety or
  • R and R form together an oxo moiety or R and R form together an oxo
  • R and R form together an oxo moiety, preferably R , R , R , R 4 '", R 5 , R 5 , R 5 " and R 5 "'represent H or oxo;
  • R 6 represents
  • alkyl the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; preferably methyl or -CH 2 - CH 2 -OH;
  • R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, iPr, tBu; cycloalkyl, preferably cyclopropane; alkene, preferably ethylene; amino, preferably NMe 3 ⁇ 4 wherein R 1 groups are optionally substituted by one or more groups selected from halogen, preferably F; hydroxyl; alkoxy, preferably OMe; COOH; amino, preferably NMe 2 or NH 2 ; S0 2 Me;
  • R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, iPr, tBu; cycloalkyl; alkene; amino ; wherein R 1 groups are optionally substituted by one or more groups selected from halogen; hydroxyl; alkoxy; COOH; amino; S0 2 Me.
  • preferred compounds of Formula I are those of Formula Ia-2:
  • X 1 and X 2 represent each independently H or F;
  • M and Q represent each independently H, C1-C6 alkyl optionally substituted one or more alogen;
  • Y represents N or CH; preferably Y is N; R 4 , R 4 ', R 4 ", R 4 '", R 5 , R 5 , R 5 " and R 5 '” represent each independently H, hydroxyl, alkyl, alkoxy, haloalkyl or R 4 and R 4' form together an oxo moiety or
  • R and R form together an oxo moiety or R and R form together an oxo
  • R and R form together an oxo moiety, preferably R , R , R , R 4 '", R 5 , R 5 , R 5 " and R 5 "'represent H or oxo;
  • R 6 represents
  • alkyl the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; preferably methyl or -CH 2 -
  • R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, iPr, tBu; cycloalkyl, preferably cyclopropane; alkene, preferably ethylene; amino, preferably NMe 2; wherein R 1 groups are optionally substituted by one or more groups selected from halogen, preferably F; hydroxyl; alkoxy, preferably OMe; COOH; amino, preferably NMe 2 or NH 2 ; S0 2 Me.
  • preferred compounds of Formula Ia-2 are those of Formula Ia-2' :
  • X 1 and X2 represent each independently H or F; preferably X 1 represents F and X2 represents H;
  • Y represents N or CH; preferably Y is N;
  • R 6 represents
  • alkyl the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH; preferably methyl or -CH 2 - CH 2 -OH;
  • R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, nPr, iPr, iBu, tBu; cycloalkyl, preferably cyclopropane; alkene, preferably ethylene; amino, preferably NH 2 , NHMe or NMe 3 ⁇ 4 wherein R 1 groups are optionally substituted by one or more groups selected from halogen, preferably F; hydroxyl; alkoxy, preferably OMe; COOH; amino, preferably NMe 2 or NH 2 ; S0 2 Me.
  • R 6 represents COR 1 or wherein R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, nPr, iPr, iBu, tBu; cycloalkyl, preferably cyclopropane; alkene, preferably ethylene; amino, preferably NH 2 , NHMe or NMe 3 ⁇ 4 wherein R 1 groups are optionally substituted by one or more groups selected from halogen, preferably F; hydroxyl; alkoxy, preferably OMe; COOH; amino, preferably NMe 2 or NH 2 ; S0 2 Me.
  • R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, nPr, iPr, iBu, tBu; cycloalkyl, preferably cyclopropane; alkene, preferably ethylene; amino, preferably NH 2 , NHMe or NMe 3 ⁇ 4 wherein R 1 groups are optionally substituted by one
  • R 6 represents COR 1 , wherein R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et or nPr ; wherein R 1 groups are optionally substituted by S0 2 Me.
  • R 6 represents S0 2 R 1 , wherein R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, nPr, iPr, tBu; wherein R 1 groups are optionally substituted by one or more groups selected from halogen, preferably F; hydroxyl; alkoxy, preferably OMe; COOH; amino, preferably NMe 2 or NH 2 ; S0 2 Me.
  • R 1 represents a group selected from C1-C6 alkyl, preferably Me, Et, nPr, iPr, tBu
  • R 1 groups are optionally substituted by one or more groups selected from halogen, preferably F; hydroxyl; alkoxy, preferably OMe; COOH; amino, preferably NMe 2 or NH 2 ; S0 2 Me.
  • preferred compounds of Formula I are those of Formula Ia-3:
  • X 1 and X 2 represent each independently H or F;
  • M and Q represent each independently H, C1-C6 alkyl optionally substituted one or more halogen;
  • Y represents N or CH; preferably Y is N;
  • R 6 represents
  • alkyl the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl or COOH;
  • cycloalkyl preferably cyclopropane
  • R 1 represents a group selected from C1-C6 alkyl, preferably methyl or ethyl; cycloalkyl; alkene; amino ; wherein R 1 groups are optionally substituted by one or more groups selected from halogen,; hydroxyl; alkoxy; COOH; amino; S0 2 Me.
  • preferred compounds of Formula I are those of Formula lb:
  • X 1 and X 2 represent each independently H, halogen or haloalkyl, preferably H, F or CF 3 , more preferably H or F;
  • M and Q represent each independently H, halogen, hydroxyl, C1-C6 alkyl optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R2 , NR 1 COR2 wherein R 1 and R 2 represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl; preferably M and Q represent each independently H, methyl or CF 3 , more preferably H or methyl;
  • n an integer equal to 1, 2 or 3, preferably 1 or 2;
  • R represents H, alkyl
  • R represents H, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, COOH, CONH 2 ; cycloalkyl, halogen, hydroxyl, oxo, COR 1 , COOR 1 ,
  • R 1 and R 2 represent each independently a hydrogen atom or a group selected from C1-C6 alkyl, cycloalkyl, alkene, aryl, heteroaryl and amino, optionally substituted by one or more groups selected from halogen, hydroxyl, alkoxy, COOH, amino, S0 2 Me.
  • preferred compounds of Formula I are those of Formula Ic:
  • X 1 and X 2 represent each independently H, halogen or haloalkyl, preferably H, F or CF 3 , more preferably H or F;
  • M and Q represent each independently H, halogen, hydroxyl, C1-C6 alkyl optionally substituted one or more substituents selected from the group comprising halogen, hydroxyl, CONR 1 R1 , NR1 COR2 wherein R 1 and R 2 represent each independently a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl; preferably M and Q represent each independently H, methyl or CF 3 , more preferably H or methyl;
  • Y 3 , Y 4 , Y 5 represent each independently N or CH;
  • R 9 is absent or represents H; halogen, preferably CI; amino, preferably NH 2 .
  • At least one of Y 3 , Y 4 , Y 5 represent N.
  • Particularly preferred compounds of Formula I of the invention are those listed in Table 1 hereafter.
  • the compounds of Table 1 were named using ChemBioDraw ® Ultra version 12.0 (PerkinElmer).
  • the compounds of Formula I and subformulae thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known in the art.
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2- (diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • compositions of Formula I may be prepared by one or more of these methods:
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate
  • pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tri
  • salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
  • a basic group such as amino
  • an acidic salt i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable solvate.
  • solvates is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force.
  • pharmaceutically acceptable solvate is intended to include all acceptable solvates such as hydrates or alcoholates and the like.
  • pharmaceutically acceptable solvates of the compounds of this invention include those formed from (but not limited to) water, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, acetic acid, ethyl acetate, 1 -propyl acetate or 2-propyl acetate.
  • solvates may be prepared by standard procedures, e.g. by crystallizing or precipitating a compound of the invention in presence of a solvent such as, but not limited to, water, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, acetic acid, ethyl acetate, 1-propyl acetate or 2-propyl acetate.
  • a solvent such as, but not limited to, water, ethanol, 1-propanol, 2-propanol, 2-methyl-2-propanol, acetic acid, ethyl acetate, 1-propyl acetate or 2-propyl acetate.
  • references to compounds of formula I include references to enantiomers, salts, solvates, polymorphs, multi- component complexes and liquid crystals thereof.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of formula I.
  • salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • non-pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
  • the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
  • the compounds of Formula I can be prepared by different ways with reactions known to a person skilled in the art.
  • the invention further relates to a process (A) for manufacturing of compounds of Formula I,
  • Z 1 represents an amino-protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known by those skilled in the art; to afford compound of Formula I.
  • deprotection step of the process (A) of the invention may be performed by treatment with bases, such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate, in the presence or absence of a suitable solvent such as but not limited to methanol, ethanol, isopropanol, iert-butanol, THF, DMF, dioxane, water or a mixture thereof, at a temperature between about 20 °C to about 100 °C, preferably at about 85 °C, for a few hours, e.g. one hour to 24 h.
  • bases such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate
  • a suitable solvent such as but not limited to methanol, ethanol, isopropanol, iert-butanol, THF, DMF, dioxane, water or a mixture thereof, at a temperature between about 20 °C to about 100 °C, preferably at about 85 °C, for a few hours, e.g
  • step b) may be performed in the presence of strong acids, such as but not limited to HC1, TFA, HF, HBr, in the presence or absence of a suitable solvent such as methanol, ethanol, isopropanol, iert-butanol, THF, DMF, Dioxane, water or a mixture thereof, at a temperature between about 20 °C to about 100 °C, for a period comprised between 10 minutes and a few hours, e.g. 10 minutes to 24 h.
  • strong acids such as but not limited to HC1, TFA, HF, HBr
  • a suitable solvent such as methanol, ethanol, isopropanol, iert-butanol, THF, DMF, Dioxane, water or a mixture thereof
  • the process (A) of the invention further comprises a preliminary step, selected for step(al) or step (a2), according to the following general scheme
  • the invention relates to a first process (Al) of manufacturing of compounds of Formula I, according to the following general scheme:
  • X 1 A and X 2" are defined as above;
  • Z 1 represents an amino-protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known by those skilled in the art;
  • Z represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy); with a compound of Formula III
  • Z 3 and Z 4 represent alkyl groups, with the possibility for Z 3 and Z 4 to form together a ring; so as to obtain a compound of Formula IV,
  • step (al) of the process (Al) of the invention may be performed with or without a catalyst such as but not limited to Pd 2 (dba) 3 , Pd(PPh ) 4 , dichlorobis(triphenylphosphine)palladium(II) or 1,1'- bis(diphenylphosphino)ferrocenedichloro palladium(II), Pd(OAc) 2 , or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTol) , PPh , BINAP, P(iBu) or any other suitable phosphine ligand known to those skilled in the art.
  • step (al) of the process (Al) of the invention is preferably performed in the presence of bases such as but not limited to K 3 PO 4 , K 2 CO 3 , Na 2 C0 3 .
  • step (al) of the process (Al) of the invention is preferably performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
  • a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
  • step (al) of the process (Al) of the invention may be carried out at a temperature ranging from about 20 °C to about 180 °C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, preferably from 10 minutes to 24 h.
  • the invention further relates to a second process (A2) of manufacturing of compounds of Formula I, according to the following general scheme:
  • Z 1 represents an amino-protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known by those skilled in the art; with a compound of Formula VI z 5 A wherein
  • A is defined as above;
  • Z 5 represents an halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms
  • halogen preferably iodine, bromine or chlorine
  • alkylsulfonyloxy having 1-6 carbon atoms preferably methylsulfonyloxy or trifluoromethylsulfonyloxy
  • arylsulfonyloxy having 6-10 carbon atoms
  • step (a2) of the process (A2) of the invention may be performed in the presence of bases such as but not limited to cesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide.
  • bases such as but not limited to cesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide.
  • step (a2) of the process (A2) of the invention may be performed in the presence of a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, ie/t-butanol, THF, dioxane, dichloromethane, water.
  • a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, ie/t-butanol, THF, dioxane, dichloromethane, water.
  • step (a2) of the process (A2) of the invention may be performed in the presence or absence of catalytic amounts of appropriate iodide salts, such as but not limited to tetrabutylammonium iodide.
  • step (a2) of the process (A2) of the invention may be carried out at a temperature between about 20 °C to about 180 °C, with or without microwave irradiation, for a period comprised between 10 minutes and a few hours, e.g. 10 minutes to 24 h.
  • the invention further relates to a general process (Bl) for manufacturing of compounds of Formula I,
  • X 1 A and X 2" are defined as above;
  • Z 1 represents H or an amino-protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known by those skilled in the art;
  • Z represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy); a compound of Formula III
  • Z 3 and Z 4 represent alkyl groups, with the possibility for Z 3 and Z 4 to form together a ring; so as to obtain a compound of Formula IV,
  • step (b) of the process (Bl) of the invention may be performed as described above for step (al) of the process (Al).
  • step (b) of the process (Bl) of the invention may be performed as described above for step (b) of the process (A).
  • the invention further relates to a general process (B2) for manufacturing of compounds of Formula I,
  • Z 1 represents H or an amino-protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known by those skilled in the art; with a compound of Formula VI z 5 A wherein
  • A is defined as above;
  • Z 5 represents an halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art; so as to obtain a compound of Formula IV,
  • step (a4) of the process (B2) of the invention may be performed as described above for step (a2) of the process (A2).
  • step (b) of the process (B2) of the invention may be performed as described above for step (b) of the process (A).
  • the synthesis pathways for any individual compound of Formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
  • compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques well known by a person skilled in the art.
  • Compounds of the formula (I) and related formulae can furthermore be obtained by liberating compounds of the formula (I) from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R*-N group, in which R* denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the formula I, but carry a -COOR** group, in which R** denotes a hydroxyl-protecting group, instead of a -COOH group.
  • amino-protecting group is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups.
  • acyl group is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr.
  • alkanoyl such as acetyl, propionyl and butyryl
  • aralkanoyl such as phenylacetyl
  • aroyl such as benzoyl and tolyl
  • Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl-protecting group is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
  • the nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms.
  • hydroxyl- protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p- toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
  • the compounds of the formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - by using for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • strong inorganic acids such as hydrochloric acid, perchloric acid or sulfuric acid
  • strong organic carboxylic acids such as trichloroacetic acid, TFA or sulfonic acids, such as benzene- or p-toluenesulfonic acid.
  • Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).
  • the BOC, OtBu and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HC1 in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.
  • Protecting groups which can be removed hydrogenolytically can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon).
  • a catalyst for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon.
  • Suitable solvents are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at 20-30°C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2- dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (
  • Esters can be hydrolysed, for example, using HC1, H 2 SO 4 , or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C.
  • Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60°C and +30°C.
  • an inert solvent such as dichloromethane or THF
  • a base such as triethylamine or pyridine
  • the invention is further directed to the use of the compounds of the invention or pharmaceutically acceptable enantiomers, salts and solvates thereof as TD02 inhibitors.
  • the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, as TD02 inhibitors. Accordingly, in another aspect, the invention relates to the use of these compounds or enantiomers, salts and solvates thereof for the synthesis of pharmaceutical active ingredients, such as TD02 inhibitors.
  • the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, for increasing immune recognition and destruction of the cancer cells.
  • compounds of the invention are therefore useful as medicaments, in particular in the prevention and/or treatment of cancer.
  • compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity.
  • the invention further relates to a method for treatment or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • TD02 expression has been demonstrated in neurons, brain vasculature and additionally in the case of schizophrenia in astroglial cells (Miller C et al., 2004, Neurobiology Dis, 15(3):618-29).
  • the kynurenine pathway is now considered as a therapeutic target in cognitive diseases like bipolar disorder or Tourette syndrome and neurodegenerative disorders like Alzheimer, motor neuron disease like Amyotrophic lateral sclerosis, Multiple sclerosis, Huntington or Parkinson's disease (Stone TW, 2013, Br J of Pharmacol, 169(6): 1211-27; Wu et al, 2013, Plos One, 8(4):e59749; Fiivesi et al, 2012, J Neural Transm, 119(2):225-34; Widner et al, 2002, J Neural Transm, 109(2): 181-9; Comings et al, 1996, Pharmacogenetics, 6(4):307-18; Forrest 2010, J Neurochem, 112(1): 112-22).
  • T cell hyporesponsiveness has been recently associated with the Tryptophan catabolic pathway in HIV-infected patients with possibly extension to other chronic infectious diseases like e.g. Hepatitis C.
  • the cancer may be metastatic or non-metastatic.
  • the cancer may be may be familial or sporadic.
  • the cancer is selected from the group consisting of: leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumours and benign and malignant non- solid tumours.
  • solid tumours include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen's disease and Paget' s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumour), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, baso
  • non- solid tumours include but are not limited to hematological neoplasms.
  • a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
  • Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias).
  • Lymphomas include, for example, Hodgkin's disease, non- Hodgkin's lymphoma lymphomas, and lymphocytic lymphomas).
  • Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
  • compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic carcinoma, gynaecological cancers (ovarian carcinoma, cervical cancer, endometrial cancer).
  • a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic
  • compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic carcinoma.
  • a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic carcinoma.
  • compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of a cancer selected gynaecological cancers such as for example ovarian carcinoma, cervical cancer, endometrial cancer.
  • compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of a cancer selected from hepatocarcinoma and glioblastoma.
  • the invention further relates to a method for treatment or prevention of a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic carcinoma, gynaecological cancers (ovarian carcinoma, cervical cancer, endometrial cancer), which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung
  • the invention further relates to a method for treatment or prevention of a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, pancreatic carcinoma, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • a cancer selected from bladder carcinoma, hepatocarcinoma, melanoma,mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myelo
  • the invention further relates to a method for treatment or prevention of a cancer selected from gynaecological cancers such as for example ovarian carcinoma, cervical cancer, endometrial cancer; which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • a cancer selected from gynaecological cancers such as for example ovarian carcinoma, cervical cancer, endometrial cancer
  • the method for treatment or prevention is a method for treatment or prevention of a cancer selected from hepatocarcinoma and glioblastoma, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
  • the invention also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable enantiomer, salt and solvate thereof to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the compounds of the invention are especially useful in the treatment and/or prevention of cancer.
  • the compounds of the invention are especially useful in the treatment and/or prevention of cancer.
  • the invention further provides the use of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for treating and/or preventing cancer.
  • a method for modulating TD02 activity in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
  • compositions comprising a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable enantiomer, salt and solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof, as active ingredient.
  • a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for modulating TD02 activity in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
  • the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propy
  • the formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc..
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • the active compound of the invention may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
  • halogen means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H2 n+ i wherein n is a number greater than or equal to 1.
  • alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms.
  • Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g.
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • Non-limiting examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoro methyl and the like.
  • cycloalkyl as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
  • Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
  • heterocyclyl where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocyclyl".
  • heterocyclyl as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi- ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include piperidinyl, azetidinyl, tetrahydropyranyl, piperazinyl, imidazolinyl, morpholinyl, oxetanyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, indolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, pyrrolizinyl.
  • alkene refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms. Examples of alkenyl groups are ethenyl, 2- propenyl, 2-butenyl, 3- butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
  • Non- limiting examples of aryl comprise phenyl, biphenylyl, biphenylenylnaphthalenyl, indenyl.
  • heteroaryl refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.
  • Non-limiting examples of such heteroaryl include: pyridazinyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quin
  • heteroarylalkyl refers to any group -alkyl-heteroaryl.
  • alk lheteroaryl refers to any group -heteroaryl-alkyl.
  • alkoxy refers to any group O-alkyl.
  • haloalkoxy refers to any group O-haloalkyl.
  • amino refers to a -NH 2 group or any group derived thereof by substitution of one nor two hydrogen atom by an organic aliphatic or aromatic group.
  • groups derived from -NH 2 are alkylamino groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.
  • amino refers to NH 2 , NHMe or NMe 2 .
  • amino-protecting group refers to a protecting group for an amine function. According to a preferred embodiment, the amino-protecting group is selected in the groups comprising: arylsulphonyl, tert-butoxy carbonyl, methoxymethyl, para-methoxy benzyl or benzyl.
  • the leaving group refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • the leaving group is selected in the groups comprising: halogen, preferably iodine, bromine or chlorine; alkylsulfonyloxy having 1-6 carbon atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy; or arylsulfonyloxy having 6-10 carbon atoms, preferably phenyl- or p-tolylsulfonyloxy.
  • solvate is used herein to describe a compound in this invention that contains stoichiometric or sub- stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol.
  • hydrate refers to when the said solvent is water.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, predrugs and prodrugs thereof and isotopically- labeled compounds of Formula I.
  • the invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
  • prodrug as used herein means the pharmacologically acceptable derivatives of compounds of Formula I, such as for example esters, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.
  • predrug means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.
  • patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure.
  • human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • stage of development i.e. neonate, infant, juvenile, adolescent, adult.
  • treatment as used herein, are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
  • therapeutically effective amount means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.
  • administration or a variant thereof (e.g. "administering", means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
  • the microwave chemistry was performed on a single mode microwave reactor Initiator Microwave System EU from Biotage.
  • Preparative HPLC purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a XbridgeTM Prep CI 8 OBD column 19x150 mm 5 ⁇ , unless otherwise reported. All HPLC purifications were performed with a gradient of CH 3 CN /H 2 0/NH 4 HC0 3 (5 mM), CH 3 CN /H 2 0/TFA (0.1%), or CH 3 CN /H 2 0/NH 3 H 2 0 (0.1%).
  • reaction mixture was stirred at 90 °C for 12 hours.
  • the mixture was filtered through Celite and washed with EtOAc (50 mL).
  • Step 2 A mixture of crude 3-(3,5-dimethyl-lH-pyrazol-4-yl)-6-fluoro-l-(phenylsulfonyl)-lH- indole and iert-butyl 4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-3,5-dimethyl-lH- pyrazole-l-carboxylate (Step 1; 5.70 g) in HCl/dioxane (20 mL; 80 mmol; 4.0 M) was stirred at 30 °C for 2 hours.
  • the combined organic layers were washed with brine (20 mLx2), dried over anhydrous Na 2 S0 4 , filtered, and concentrated to afford 216 mg (82%) of the title compound as a gray solid, which was used directly without further purification.
  • Step 1 tert-butyl 3-(4-(6-fluoro-l H-indol-3-yl)-l H-pyrazol-1 -yl)azetidine-l -carboxylate
  • a mixture of 6-fluoro-l-(phenylsulfonyl)-3-(lH-pyrazol-4-yl)-lH-indole (Intermediate 5; 346 mg; 1.0 mmol), iert-butyl 3-iodoazetidine-l -carboxylate (283 mg; 1.0 mmol) and NaH (100 mg; 2.5 mmol; 60% w/w) in DMF (5 mL) was heated to 120 °C for 0.5 hour in a microwave reactor.
  • reaction mixture was added NaOH (100 mg; 2.50 mmol) in water (0.5 mL) and stirred for 0.5 hour at 85 °C.
  • Step 2 To a solution of iert-butyl 3-(4-(6-fluoro-lH-indol-3-yl)-lH-pyrazol-l-yl)azetidine-l- carboxylate (Step 1; 220 mg; 0.62 mmol) in MeOH (10 mL) was added saturated HCl in Et 2 0 (5 mL). The mixture was stirred for 3 h, concentrated, and purified by preparative HPLC to afford 27.8 mg (18%) of the title compound as a white solid.
  • Step 1 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)azetidine-l- carboxamide
  • Step 1 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-N- methylazetidine-l -carboxamide
  • Step 1 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)propanamide
  • 6-fluoro-l-(phenylsulfonyl)-3-(lH-pyrazol-4-yl)-lH-indole (Intermediate 5; 225 mg; 0.66 mmol)
  • 3-bromopropanamide (302 mg; 1.99 mmol), KI (20 mg; 0.12 mmol) and K 2 C0 3 (274 mg; 1.98 mmol) in CH 3 CN (20 mL) and DMF (10 mL) was stirred at 100 °C overnight.
  • the reaction mixture was cooled to r.t., filtered, and concentrated to afford 272 mg (100%) of the title compound as a white solid, which was used directly without further purification.
  • Step 1 3-(4-(5,6-difluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)propanamide
  • Step 1 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-3,5-dimethyl-lH-pyrazol-l- yl)propanamide
  • 3-(3,5-dimethyl-lH-pyrazol-4-yl)-6-fluoro-l-(phenylsulfonyl)-lH-indole (Intermediate 50; 100 mg; 0.27 mmol), 3-bromopropanamide (411 mg; 2.70 mmol), KI (45 mg; 0.27 mmol), and K 2 C0 3 (186 mg; 1.35 mmol) in DMF (3.0 mL) was stirred at 70 °C for 16 hours.
  • Step 1 6-fluoro-3-(l-(2-(4-methylpiperazin-l-yl)ethyl)-lH-pyrazol-4-yl)-l- (phenylsulfonyl)-l H -indole
  • Step 1 4-(2-(4-( 6-fluoro-l -(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l - yl)ethyl)morpholine
  • Step 1 N-(2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)ethyl)acetamide
  • Step 1 l-(2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)ethyl)urea
  • Step 2 Following the general method as outlined in the synthesis of compound 70, starting from l-(2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)ethyl)urea (Step 1; 161 mg), 41 mg (60%) of the title compound was obtained as a yellow solid after purification by preparative TLC (EtOAc).
  • Step 1 N-(2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)ethyl)methane sulfonamide
  • Step 1 2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)ethanol
  • Step 1 l-(4-(2-(4-( 6-fluoro-l -(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l - yl)ethyl)piperazin-l-yl)ethanone
  • Step 1 l-(2-(4-( 6-fluoro-l -(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l - yl)ethyl)pyrrolidin-2-one
  • Step 1 6-fluoro-3-(l-(2-(methylsulfonyl)ethyl)-lH-pyrazol-4-yl)-l-(phenylsulfonyl)-lH- indole
  • Step 1 3-( 3, 5 -dimethyl- 1 -(2-( methylsulfonyl)ethyl)-lH-pyrazol-4-yl)-6-fluoro-l -
  • Step 2 Following the general method as outlined in the synthesis of compound 3, starting from 3 -(3, 5 -dimethyl- l-(2-(methylsulfonyl)ethyl)- lH-pyrazol-4-yl)-6-fluoro- 1- (phenylsulfonyl)-lH-indole (Step 1; 47 mg; 0.10 mmol), 18 mg (54%) of the title compound was obtained as a white solid after purification by preparative HPLC.
  • Step 1 methyl 3-(4-( 6-fluoro-l -(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l -yl)-2 - methylpropanoate
  • Step 2 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-2- methylpropanoic acid
  • Step 2 starting from methyl 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)-2-methylpropanoate (Step 1; 341 mg; 0.77 mmol), 329 mg (100%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
  • Step 3 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-2- methylpropanamide
  • Step 1 3-(l-(2,2-diethoxyethyl)-lH-pyrazol-4-yl)-6-fluoro-l-(phenylsulfonyl)-lH-indole
  • Step 3 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-2-hydroxy propanenitrile
  • Step 4 3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-2- hydroxypropanamide
  • Step 1 2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)acetamide
  • Step 1 ethyl 2-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)acetate
  • 6-fluoro-l-(phenylsulfonyl)-3-(lH-pyrazol-4-yl)-lH-indole (Intermediate 5; 1.00 g; 2.93 mmol) and K 2 C0 3 (1.30 g; 9.41 mmol) in DMF (40 mL) was added ethyl bromoacetate (1.50 g; 8.98 mmol).
  • Step 1 6-fluoro-l -(phenylsulfonyl)-3-( 1 -(( 1 -(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)- 1 H-pyrazol-4-yl)-l H-indole
  • Step 1 6-fluoro-3-(l-((l-(2-fluoroethyl)piperidin-4-yl)methyl)-lH-pyrazol-4-yl)-l- (phenylsulfonyl)-l H -indole
  • 6-fluoro-l-(phenylsulfonyl)-3-(l-(piperidin-4-ylmethyl)-lH-pyrazol-4-yl)-lH- indole (Intermediate 21; 111 mg; 0.25 mmol) and l-bromo-2-fluoroethane (64 mg; 0.50 mmol), 122 mg (100%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
  • Step 1 2-(4-((4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)methyl)piperidin-l -yl)ethanol
  • 6-fluoro-l-(phenylsulfonyl)-3-(l-(piperidin-4-ylmethyl)-lH-pyrazol-4-yl)-lH- indole (Intermediate 21; 200 mg; 0.46 mmol), 200 mg (91%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
  • Step 1 ethyl 2-(4-((4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)methyl)piperidin-l -yl)acetate
  • 6-fluoro-l-(phenylsulfonyl)-3-(l-(piperidin-4-ylmethyl)-lH-pyrazol-4-yl)-lH- indole (Intermediate 21; 185 mg; 0.42 mmol)
  • 330 mg of the title compound was obtained as a yellow oil after purification by reverse phase flash chromatography.
  • LC-MS mlz 525 [M + H] + .
  • Step 1 methyl 4-(4-((4-( 6-fluoro-l -(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l - yl)methyl)piperidin-l-yl)-4-oxobutanoate
  • Step 1 l-(4-((4-( 6-fluoro-l -(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l - yl)methyl)piperidin-l-yl)ethanone
  • Step 1 3-(l-((l-cyclopropylpiperidin-4-yl)methyl)-lH-pyrazol-4-yl)-6-fluoro-l- (phenylsulfonyl)-l H -indole
  • Step 1 6-fluoro-3-( methylsulfonyl)piperidin-4-yl)methyl)-lH-pyrazol-4-yl)-l - (phenylsulfonyl)-l H -indole
  • Step 2 tert-butyl 4-((4-(6-fluoro-lH-indol-3-yl)-3,5-dimethyl-lH-pyrazol-l- yl)methyl)piperidine-l -carboxylate
  • Step 3 Following the general method as outlined in synthesis of compound 2, starting from tert-butyl 4-((4-(6-fluoro-lH-indol-3-yl)-3,5-dimethyl-lH-pyrazol-l- yl)methyl)piperidine-l -carboxylate (Step 2; 96 mg; 0.23 mmol), 45 mg (55%) of the title compound was obtained as a yellow solid after purification by preparative HPLC (HC1 additive).
  • Step 1 tert-butyl 4-((4-(6-fluoro-l H-indol-3-yl)-3-methyl-l H-pyrazol-1 - yl)methyl)piperidine-l -carboxylate
  • Step 2 Following the general method as outlined in synthesis of compound 2, starting from iert-butyl 4-((4-(6-fluoro-lH-indol-3-yl)-3-methyl-lH-pyrazol-l-yl)methyl)piperidine- 1-carboxylate (Step 1; 150 mg; 0.36 mmol), 50 mg (44%) of the title compound was obtained as a white solid after purification by preparative HPLC.
  • Step 2 Following the general method as outlined in synthesis of compound 2, starting from iert-butyl 4-((4-(6-fluoro-lH-indol-3-yl)-5-methyl-lH-pyrazol-l-yl)methyl)piperidine- 1-carboxylate (Step 1; 150 mg; 0.36 mmol), 15 mg (13%) of the title compound was obtained as a white solid after purification by preparative HPLC.
  • Step 1 6-fiuoro-l -(phenylsulfonyl)-3-( 1 -((tetrahydro-2H-pyran-4-yl)methyl)-lH- pyrazol-4-yl)-l H-indole
  • Step 2 Following the general method as outlined in the synthesis of compound 70, starting from 6-fluoro-l-(phenylsulfonyl)-3-(l-((tetrahydro-2H-pyran-4-yl)methyl)-lH-pyrazol- 4-yl)-lH-indole (Step 1; 398 mg; 0.90 mmol), 102 mg (38%) of the title compound was obtained as a white solid after purification by preparative HPLC.
  • Step 1 4-((4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)methyl)tetrahydro-2H-pyran-4-ol
  • Step 1 trans-3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)cyclobutanecarboxamide
  • Step 1 cis-3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-N- methylcyclobutanecarboxamide
  • Step 1 trans-3-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)-N- methylcyclobutanecarboxamide
  • Coppound 68 cis -4- (4- (6-fluoro- lH-indol-3- yl) - lH-p yrazol- 1 - vDcyclohexanol
  • Step 1 4-(4-(6-fluoro-lH-indol-3-yl)-lH-pyrazol-l-yl)cyclohexanone
  • Step 1 1 ,1 ,1 -trifluoro-3-(l -(phenylsulfonyl)-lH-indol-3-yl)propan-2-one
  • 2-(l-(phenylsulfonyl)-lH-indol-3-yl)acetic acid (1.50 g; 4.76 mmol) and trifluoroacetic anhydride (3.0 mL; 22 mmol) in toluene (150 mL) at 0 °C
  • pyridine 2.4 mL; 30 mmol
  • reaction mixture was quenched with ice-water (200 mL) and extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 S0 4 , filtered, concentrated, and purified by reverse phase flash chromatography and preparative HPLC to afford 0.50 g (29%) the title compound as a yellow oil.
  • Step 2 4,4,4-trifluoro-3-oxo-2-(l-(phenylsulfonyl)-lH-indol-3-yl)butanal
  • Step 1 2-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH ndol-3-yl)-lH-pyrazol-l-yl)piperidin- l-yl)ethanol
  • Step 2 Following the general method as outlined in the synthesis of compound 70, starting from 2-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)piperidin-l- yl)ethanol (Step 1; 148 mg; 0.32 mmol), 36mg (35%) of the title compound was obtained as a yellow solid after purification by preparative HPLC.
  • Step 1 l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)piperidin- l-yl)-5 '-methoxypropan-l-one
  • Step 2 Following the general method as outlined in the synthesis of compound 70, starting from l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)piperidin-l- yl)-3-methoxypropan-l-one (Step 1; 440 mg), 30 mg (13 %) of the title compound was obtained as a white solid after purification by preparative HPLC.
  • Step 2 Following the general method as outlined in the synthesis of compound 70, starting from l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)piperidin-l- yl)propan-l-one (Step 1; 310 mg; 0.65 mmol), 50 mg (23 %) of the title compound was obtained as a white solid after purification by preparative HPLC.
  • Step 1 2-(dimethylamino)-l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH- pyrazol-1 -yl )piperidin-l -yl)ethanone
  • Step 1 2-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH ndol-3-yl)-lH-pyrazol-l-yl)piperidin- l-yl)-2-oxoethyl acetate
  • Step 1 l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH ndol-3-yl)-lH-pyrazol-l-yl)piperidin- 1 -yl)-2-methoxyethanone
  • 6-fluoro- l-(phenylsulfonyl)-3-(l-(piperidin-4-ylmethyl)-lH-pyrazol-4-yl)-lH- indole (Intermediate 21; 188 mg; 0.43 mmol) and 2-methoxyacetic acid (41 mg; 0.46 mmol)
  • 260 mg of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (EtOAc).
  • Step 1 l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH ndol-3-yl)-lH-pyrazol-l-yl)piperidin- 1 -yl)-2-methylpropan- 1 -one
  • Step 1 l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l-yl)piperidin- 1 -yl)-2,2-dimethylpropan-l -one
  • 6-fluoro- l-(phenylsulfonyl)-3-( l-(piperidin-4-yl)- lH-pyrazol-4-yl)- lH-indole hydrochloride (Intermediate 17; 200 mg; 0.47 mmol) and pivaloyl chloride (0.12 mL; 0.98 mmol), 250 mg (>100 %) of the title compound was obtained as a yellow solid, which was used directly without further purification.
  • Step 1 cyclopropyl(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH-indol-3-yl)-lH-pyrazol-l- yl)piperidin-l -yl)methanone
  • 6-fluoro- l-(phenylsulfonyl)-3-( l-(piperidin-4-yl)- lH-pyrazol-4-yl)- lH-indole hydrochloride (Intermediate 17; 300 mg; 0.65mmol) and cyclopropanecarboxylic acid (122 mg; 1.42 mmol) in DMF (6 mL), 345 mg of the title compound was obtained as a yellow oil, which was used directly without further purification.
  • Step 1 l-(4-(4-(6-fluoro-l-(phenylsulfonyl)-lH ndol-3-yl)-lH-pyrazol-l-yl)piperidin- 1 -yl)ethanone
  • Et 3 N (0.23 mL; 1.65 mmol
  • acetyl chloride 87 mg; 1.1 mmol
  • the reaction mixture was stirred for 1 h and concentrated to afford 256 mg (100%) of the title compound as a white solid, which was used directly without further purification.
  • Step 1 6-fluoro-3-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-l-(phenylsulfonyl)-lH- indole
  • Step 2 Following the general method as outlined in the synthesis of compound 70, starting from 6-fluoro-3-(l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)-l-(phenylsulfonyl)-lH- indole (Step 1; 240 mg), 58 mg (37%) of the title compound was obtained as a white solid after purification by preparative HPLC.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Virology (AREA)
  • Psychology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Psychiatry (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pain & Pain Management (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Molecular Biology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP14796082.7A 2013-11-08 2014-11-07 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use Withdrawn EP3066090A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14796082.7A EP3066090A1 (en) 2013-11-08 2014-11-07 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US14/076,016 US9126984B2 (en) 2013-11-08 2013-11-08 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
EP13192224 2013-11-08
BE201400845 2014-11-03
PCT/EP2014/074099 WO2015067782A1 (en) 2013-11-08 2014-11-07 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
EP14796082.7A EP3066090A1 (en) 2013-11-08 2014-11-07 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use

Publications (1)

Publication Number Publication Date
EP3066090A1 true EP3066090A1 (en) 2016-09-14

Family

ID=53040940

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14796082.7A Withdrawn EP3066090A1 (en) 2013-11-08 2014-11-07 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use

Country Status (4)

Country Link
EP (1) EP3066090A1 (ja)
JP (1) JP2016535097A (ja)
CA (1) CA2929650C (ja)
WO (1) WO2015067782A1 (ja)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI695831B (zh) 2014-09-13 2020-06-11 香港商南北兄弟藥業投資有限公司 Ｃｒｔｈ２拮抗劑化合物及其用途
JP6954924B2 (ja) * 2016-04-29 2021-10-27 バイエル・ファルマ・アクティエンゲゼルシャフト Ｎ−｛６−（２−ヒドロキシプロパン−２−イル）−２−［２−（メチルスルホニル）エチル］−２ｈ−インダゾール−５−イル｝−６−（トリフルオロメチル）ピリジン−２−カルボキサミドの多形体
EP3269714A1 (en) 2016-07-13 2018-01-17 Netherlands Translational Research Center B.V. Inhibitors of tryptophan 2,3-dioxygenase
EP3515914A4 (en) 2016-09-24 2020-04-15 BeiGene, Ltd. NEW IMIDAZO [1,5-A] PYRIDINES SUBSTITUTED IN POSITION 5 OR 8 AS INDOLEAMINE AND / OR TRYPTOPHANE 2,3-DIOXYGENASES
US20230391786A1 (en) * 2022-06-02 2023-12-07 Eli Lilly And Company cGAS INHIBITORS

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2862647B1 (fr) * 2003-11-25 2008-07-04 Aventis Pharma Sa Derives de pyrazolyle, procede de preparation et intermediaires de ce procede a titre de medicaments et de compositions pharmaceutiques les renfermant
GB0516156D0 (en) * 2005-08-05 2005-09-14 Eisai London Res Lab Ltd JNK inhibitors
US20110159017A1 (en) * 2008-04-11 2011-06-30 Ludwig Institute For Cancer Research Ltd. Trytophan catabolism in cancer treatment and diagnosis
SG182247A1 (en) 2009-05-27 2012-08-30 Hoffmann La Roche Bicyclic indole-pyrimidine pi3k inhibitor compounds selective for p110 delta, and methods of use
CN103947645B (zh) 2009-10-12 2016-07-06 拜尔农作物科学股份公司 作为杀虫剂的1-(吡啶-3-基)-吡唑和1-(嘧啶-5-基)-吡唑
CA2803802A1 (en) * 2010-06-23 2011-12-29 Vertex Pharmaceuticals Incorporated Pyrrolo- pyrazine derivatives useful as inhibitors of atr kinase

Also Published As

Publication number Publication date
JP2016535097A (ja) 2016-11-10
CA2929650A1 (en) 2015-05-14
WO2015067782A1 (en) 2015-05-14
CA2929650C (en) 2017-08-22

Similar Documents

Publication Publication Date Title
US9126984B2 (en) 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
US20160263087A1 (en) Novel 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
AU2016231832B2 (en) Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
US9758505B2 (en) 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
US10544095B2 (en) 3-indol substituted derivatives, pharmaceutical compositions and methods for use
WO2015140717A9 (en) Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
AU2016217851A1 (en) 1-(het)arylsulfonyl-(pyrrolidine or piperidine)-2-carboxamide derivatives and their use as TRPA1 antagonists
CA2929650C (en) 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
US20150266857A1 (en) Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
CN117177974A (zh) 含咪唑稠环类衍生物、其制备方法及其在医药上的应用
KR20240006494A (ko) 퀴녹살린 유도체 및 이의 사용
KR20220090553A (ko) Ssao 억제제 및 그의 용도
BE1021253B1 (fr) Nouveaux derives substitues de 3-indol, compositions pharmaceutiques et methode d'utilisation
WO2021202775A1 (en) N-(heterocyclyl and heterocyclylalkyl)-3-benzylpyridin-2-amine derivatives as sstr4 agonists
BE1021252B1 (fr) Nouveaux derives de 3-(indol-3-yl)-pyridine, compositions pharmaceutiques et methodes d'utilisation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20160608

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20180602